ABSTRACT: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed.
729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken.
The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system.
Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.
Journal of Neurology Neurosurgery & Psychiatry 03/2002; 72(2):184-7. · 4.76 Impact Factor
ABSTRACT: To assess the potential contribution of genetic factors to clinical phenotype in multiple sclerosis.
Using a cohort of 262 pairs of coaffected siblings from 250 families with multiple sclerosis, intersibling concordance analysis was used to explore underlying genetic mechanisms in disease pathogenesis by assessing parameters of disease course, clinical presentation, age and year of onset, and measures of disability and handicap.
Adjusted intraclass correlation coefficients were not significant for either age of onset or for year of first symptom. One third of sibling pairs were concordant for presenting symptom (81/262), a result that was non-significant. However, course type was identical in 50% of the sibling pairs (kappa=0.17 (95% confidence interval (95% CI) 0.08 to 0.26)) indicating a significant result. Severity of the disease at assessment, using the Kurtzke and CAMBS scales, demonstrated that whereas there was no agreement for relapse rate in the previous year within the sibship, there was significant concordance for measures of disability (kappa=0.11 (95% CI 0.04 to 0.19)), progression (kappa=0.09 (95% CI 0.01 to 0.18)) and handicap (kappa=0.08 (95% CI 0.02 to 0.14)).
Within a sibship, the clinical presentation tends to be different. However, once established, concordance is more likely to be seen for the ultimate course, leading in the end to similar disability and handicap scores. These results are consistent with the hypothesis that genes influence both disease susceptibility and evolution in multiple sclerosis.
Journal of Neurology Neurosurgery & Psychiatry 01/2002; 71(6):757-61. · 4.76 Impact Factor
ABSTRACT: Although the exact etiology of MS remains elusive, there is good evidence that genetic factors play an important role. These factors are likely to be polygenic, exerting both independent and interactive effects on the expression of MS. They may determine susceptibility and/or shape the clinical course.
The authors studied clinical phenotype in 245 concordant parent-child pairs recruited from a national register of familial disease over a 10-year period. Data were examined in order to determine the effect of parental sex on expression of disease in the offspring.
Allowing for the observed sex ratio of 2.6 F:1 M in this group of patients, sex pairings of parents and offspring were close to those expected. When assessed independently there was no evidence that either the sex of the affected offspring or the line of inheritance influenced disability, age at onset, or disease course. However, trends were observed toward greater disability and an increased frequency of primary progressive disease in offspring of affected fathers and an earlier age at onset in offspring of affected mothers. The highest mean Expanded Disability Status Scale score was observed in male offspring of affected fathers (5.64) and this group was also more likely to have primary progressive disease (OR 1.92). Thirty-one percent of families had an additionally affected offspring with no preferential maternal or paternal transmission.
In offspring of concordant parent-child families with MS who are at high risk of inheriting increased numbers of susceptibility genes there is no evidence for a parent of origin effect distorting sex ratios in affected offspring, but parent of origin may influence disability and disease course as well as increasing the risk to additional offspring within the same family. The mechanism of these effects is not clear but may result from interactions between genes encoded at different loci (epistasis), which each independently influence susceptibility and phenotype.
Neurology 08/2001; 57(2):290-5. · 8.31 Impact Factor